New Developments in Thyroid Cancer

Transcription

1 New Developments in Thyroid Cancer Eric J. Sherman, MD Professor Vice-Chair for Clinical Operations Chief, Division of Head and Neck Surgery Departments of Otolaryngology, Radiation Oncology, and Immunology Co-Leader, Cancer Immunology Program Memorial Sloan-Kettering Cancer Center New York, NY

2 Disclosure Dr. Sherman has the following relevant financial relationships with commercial interests to disclose: Consultant: Bristol-Myers Squibb

3 Classification & Incidence of Thyroid Cancer Follicular cell origin Differentiated Papillary 80% Follicular 10% Hurthle cell 3-5% Undifferentiated Anaplastic 1-2% Parafollicular cell origin Medullary 5%

4 Rising Incidence of Thyroid Cancer

5 Thyroid Cancer Research Lack of research for years ASCO Annual Meetings abstracts of clinical studies involving thyroid cancer (chemotherapy related) No Abstracts Abstracts

6 RAI-REFRACTORY DISEASE 25-50% of metastatic thyroid cancers lose iodine concentrating ability Standard chemotherapy has disappointing response rates and significant toxicity Not well studied; limited prospective evidence

7 Doxorubicin: Single-agent Activity Reference Response Rate Gottlieb et al /2 (100%) Frei et al /19 (37%) Gottlieb and Hill /15 (33%) O'Bryan et al /9 (22%) Kolaric et al /16 (31%) Burgess and Hill /19 (37%) Leeper and Shimaoka /7 (28%) Benker and Reinwein /11 (73%) Pacini et al /5 (90%) Droz et al /6 (0%) Total 42/109 (38.5%)

8 Role of Molecularly Targeted Agents in Thyroid Cancer

9 Targets in Thyroid Cancer Angiogenesis pathway (all subtypes) Follicular Cell Derived Thyroid Cancer MAPK pathway (RET-BRAF-RAS) PI3K/AKT/mTOR (RET-RAS-PTEN- PIK3CA-AKT1) Medullary Thyroid Cancer RET

10 Medullary Thyroid Cancer RET

11 Medullary Thyroid Cancer Synaptophys in Chromograni n CEA Calcitonin

12 MTC: hereditary vs sporadic? 20-25% of MTC are hereditary Germline mutations in RET protooncogene (Rearranged during Transfection) Autosomal dominant inheritance Three subtypes: MEN2A MEN2B Familial medullary thyroid cancer (FMTC)

13 Sporadic MTC Frequency of RET mutations Elisei, R. et al. J Clin Endocrinol Metab 2008;93:

14 Vandetanib Tyrosine Kinase Inhibitor targeting VEGF-R 1 to 3, PDGFR, RET Recently approved by the US-FDA for advanced MTC First-in-class agent to be approved for this disease setting

15 Vandetanib Phase III ZETA Trial Patients with unresectable locally advanced or metastatic MTC (N=331) 2:1 randomization Vandetanib 300 mg/day n=231 Placebo n=100 Follow for progression Follow for progression Discontinue blinded treatment at progression Optional open-label vandetanib 300 mg/day Follow for survival Provided By Sam Wells

16 Progression-free survival PFS (primary endpoint) Vandetanib 300 mg Placebo Hazard ratio = 0.46 ( ); P< Median: not reached (vandetanib); 19.3 months (placebo) At risk (n) Vandetanib Placebo Time (months) Hazard ratio <1 favors vandetanib

17 Objective tumor assessments Intention to treat analysis* Vandetanib 300 mg (n=231) Placebo (n=100) Objective response rate 45% (104) 13% (13) Odds ratio (95% CI) 5.48 ( ), P< of 13 responses on the placebo arm occurred while patients were receiving vandetanib in the open-label phase Objective responses were durable; median duration of response not reached at 24 months of follow-up Odds ratio >1 favors vandetanib *Including all scans until progression according to central read Provided By Sam Wells

18 XL184 Preclinical Rationale Potent inhibitor of MET, VEGFR2, and RET Active against common mutants of MET and RET Promotes angiogenesis, tumor cell proliferation, migration, and survival MET VEGFR2 Induces angiogenesis RET Involved in the pathogenesis of MTC; Partially controls MET expression

19 % Tumor Change Best Timepoint Response for 35 MTC Patients with Measurable Disease, Per Investigator Report a No activating RET mutations Activating RET mutations RET status unknown a MTC patient with G469A BRAF mutation Confirmed partial response (PR) per RECIST * Note: One patient discontinued prior to having post-baseline scan * * * * * * * * * * 49% (17/35) experienced a tumor shrinkage of > 30% on at least one post-baseline scan 29% (10/35) of patients with measurable disease had confirmed PR Tumor shrinkage was observed regardless of RET mutation status

20 % Tumor Change Best Timepoint Response for TKI Naïve versus TKI Pre-Treated MTC Patients TKI Naïve (n = 19) TKI Pre-Treated (n = 15) V V V a V TKI, tyrosine kinase inhibitor; V, vandetanib a Patient was on randomized trial and may have received vandetanib Three patients with known prior vandetanib therapy had tumor shrinkage 19

21 Angiogenesis Inhibition

22 VEGF and Thyroid Cancer VEGF levels Recurrence DFS Malignant thyroid tissue vs. Benign thyroid tissue Yu X et al. Clin Cancer Res 2005;11:

23 Sorafenib Tyrosine Kinase Inhibitor Target VEGF-R 1 to 3, PDGF receptor, RET In addition it is a RAF kinase inhibitor Currently FDA-approved for the treatment of kidney and liver cancers

24 Sorafenib University of Pennsylvania Group: Iodine-Refractory Thyroid Cancer Papillary (60%) Follicular Cell/Hurthle Cell (30%) Anaplastic/poorly differentiated (7%) Medullary (3%) Number: 30 (although continues to accrue) Phase II Study; Sorafenib 400 mg po bid Accrual between 2/28/2006 and 9/13/2007 Gupta-Abramson, V. et al. J Clin Oncol; 26:

25 Sorafenib University of Pennsylvania Complete Response Rate 0 (0%) Partial Response Rate 7 (23%) Stable Disease 16 (53%) Median Progression-Free Survival: 79 Weeks Gupta-Abramson, V. et al. J Clin Oncol; 26:

26 Sorafenib Ohio State RAI-Refractory Thyroid Cancer Group A: Papillary thyroid cancer, chemotherapy naïve, and available archival tissue 19 total patients Group B: All others 22 with papillary thyroid cancer 37 total patients

27 Response Rates PTC, chemonaïve (33 pts) Ohio State PTC, prior chemo (n=8) HTC/FTC (n=11) Anaplastic (n=4) Partial Response 5 (15%) 1 (13%) 0 0 Stable Disease 19 (57%) 6 (75%) 9 (82%) 1 (25%) Progressive Disease 4 (12%) 1 (12%) 1 (9%) 3 (75%) PFS, median, months OS, median, month

28 Response Rates Ohio State versus Penn Ohio State (56 pts) U. of Penn (n=30) Partial Response 6 (11%) 7 (23%) Stable Disease 35 (63%) 16 (53%) Progressive Disease Cell Types with responses 9 (16%) 2 (3%) Papillary Papillary, Follicular, Hurthle

29 Lenvatinib (E7080) Background Lenvatinib (Adopted USAN for E7080): Small molecule, tyrosine kinase inhibitor administered orally by once daily continuous dosing Targets VEGFR1-3, FGFR 1-4, RET, PDGFR and KIT Sherman et al. ASCO 2011 abstract 5503

30 Response Rate Investigator Assessment Prior VEGFRtargeted therapy N=17 (%) No prior VEGFRtargeted therapy N=41 (%) Overall N=58 (%) Complete response (CR) Partial response (PR) (95% CI) 7 (41%) 22 (54%) 29 (50%) (36-63%) Stable disease (SD) 9 (53%) 17 (42%) 26 (45%) Durable SD 6 (35%) 13 (32%) 19 (33%) Progressive disease (PD) 1 (6%) 1 (2%) 2 (3%) Disease control rate (CR + PR + SD) 16 (94%) 39 (95%) 55 (95%) Sherman et al. ASCO 2011 abstract 5503

31 Differentiated Thyroid Cancers Phase II studies Multitargeted TKIs Agent # PR/CR SD Site Sorafenib 56 11% 63% Ohio State Sorafenib 25 23% 53% Univ. of Pennsylvania Sunitinib 29 28% 48% (?) Univ. of Washington Sunitinib 35 17% 74% Univ. of Chicago Pazopanib 37 49% 43% (?) Mayo Clinic Axitinib 45 31% 42% Pfizer Motesanib 93 14% 67% Amgen Lenvatinib 58 59% 36% Multi-Site Aflibercept (VEGF trap) 40 0% 83% MSKCC

32 Differentiated Thyroid Cancers Phase II studies Multitargeted TKIs Agent # PR/CR Target Sorafenib 56 11% VEGFR, PDGFR, RAF, RET Sorafenib 25 23% VEGFR, PDGFR, RAF, RET Sunitinib 29 28% VEGFR, PDGFR, c-kit, RET Sunitinib 35 17% VEGFR, PDGFR, c-kit, RET Pazopanib 37 49% VEGFR, PDGFR, c-kit, RET Axitinib 45 31% VEGFR, PDGFR, c-kit Motesanib 93 14% VEGFR, PDGFR, c-kit E % VEGFR1-3, FGFR 1-4, RET, PDGFR, c-kit Aflibercept (VEGF trap) 40 0% VEGF

33 Conclusion Many Phase II studies have been done in thyroid cancer showing activity We do not know Best agent Important target Real benefit

34 MAPK pathway in Thyroid Cancer

35 Genetic Alterations in Thyroid Cancer X (RET/PTC, TRK rearrang) TK (RET, NTRK) X X Ras B-Raf PI3K X PTEN X Akt/PKB S473 TSC2 TSC1 T308 X Cell survival, growth, RheB MEK 1/2 70% of all PTC with activated MAPK Erk 1/2 mtor mrna Translation Transcriptional Activation (Elk-1, Ets, c-jun, c-fos etc )

36 Concordance of genetic alterations in MAPK but not PI3K pathway oncogenes in patients with multiple tumor specimens Discordant 0 BRAF/RAS PIK3CA/AKT1 Concordant

37 BRAF Target

38 B-Raf Mutation Portends Worse Prognosis Xing M. Endocr. Rev., 2007.

39 PLX4032/Vemurafenib Kinase selectivity translates from biochemical to cells to tumor models Selective for BRAF V600E kinase 70 kinases screened IC 50 (nm) Selective in cellular assays V600E WT Phospho-ERK A375 COLO829 COLO205 SW620 SKMEL2 IC 50 (nm) >40,000 14,000 Selective regression of V600E tumors Selective BRAF V600E binding PLX4720 costructure [2008 PNAS] Growth V600E + PLX4032 WT + PLX4032

40 Vemurafenib Waterfall Plot in Extension Cohort Flaherty KT et al. N Engl J Med 2010;363:

41 Interim Vemurafenib phase I Kaplan-Meier plot: V600E+ vs V600E melanoma patients ( 240mg BID) % progression-free survival V600E (n=16) WT (n=5) Median PFS Days WT 44 V600E Time since first dose (days) As of May

42 V600E+ melanoma patient on 720 mg BID 85% tumor shrinkage in visceral lesions Baseline End of cycle 2 End of cycle 3 Liver Bowel Bone

43 In Phase I Study Vemurafenib 1/3 thyroid cancer pts. had response; other 2 with stable disease Median PFS = 12 months Phase II study in thyroid cancer recently started Sorafenib treated and sorafenib naïve cohorts Pre- and Post-biopsies

44 GSK Small molecule inhibitor that is selective for BRAFV600E mutation 10/16 subjects with melanoma BRAF mutation had response rate 1/2 patients with BRAF (+) thyroid cancer with response; other with 66% decrease in RECIST measurable disease

45 Summary BRAF is a logical target in thyroid cancer BRAF V600 mutation is common Early, conserved mutation New inhibitors have shown significant activity in melanomas with BRAF mutations May not have same activity in thyroid cancer Mechanisms of resistance need to be elucidated

46 Reacquisition of RAI uptake of RAIrefractory metastatic thyroid cancers by pretreatment with the selective MEK inhibitor AZD6244: A pilot study

47 Mitogen Activated Protein Kinase (MAPK) Activation Suppresses Expression of NIS in Thyroid Cancer Receptor Tyrosine Kinase Tg-rTTA/tet0-Braf V600E + Braf V600E OFF Doxycycline Braf V600E ON Ras Braf B-Raf V600E MEK 1/2 Erk 1/2 Tumor proliferation and survival NIS: Na/I - Symporter Debyani Chakravarty and Jim Fagin, JCI (in press)

48 Pharmacologic inhibition of oncogenic BRAF signaling increases RAI uptake in the dox inducible BRAF V600E model.

49 Clinical Hypothesis RTK Treatment of patients with BRAF mutant, RAI-refractory tumors with a MEK inhibitor will result in tumor reacquisition of RAI uptake and susceptibility to therapeutic 131 I. Ras B-Raf Selumetinib (AZD6244) MEK 1/2 Erk 1/2 Thyroid specific gene expression (e.g. NIS)

50 Protocol Schema (lesion absorbed dose >2,000 cgy)

51 Objective Primary Objective: To determine whether RAI uptake increases after treatment with MEK inhibitor in patients with RAI-refractory thyroid cancer Association with BRAF mutation

52 Definition of RAI-Refractory Disease 1) Index metastatic lesion non-rai avid on a diagnostic RAI scan performed up to 2 years prior to enrolment in the current study 2) RAI-avid metastatic lesion which remained stable in size or progressed despite RAI treatment 6 months or more prior to entry in the study. 3) Patients with FDG avid lesions

53 Impact of Selumetinib Upon 124 I Incorporation Patients with new/increased 124 I incorporation after selumetinib BRAF WT BRAF MUT N=17 11/17 7 (of 10 WT) 4 (of 7 MUT) Patients who received therapeutic RAI 7/11 BRAF WT 6 BRAF MUT 1

54 Grewal/Santos

55 MEK-Inhibitor Baseline Significant Acquisition of 124 I Tracer Activity within Thyroid Cancer Bone Metastases Grewal/Santos

56 Post-therapy SUVmax n= 55 lesions MEK % (+50%) (+25%) (+0%) (-25%) MEK (-50%) Pre-therapy SUVmax n= 41 lesions Desiree D Andreis

57 Best Response For Patients Treated with RAI Change in Target Lesions by RECIST (%) 0% -10% -20% -30% -40% -50% -60% -70% -80% -90% Confirmed PR Confirmed SD -100%

58 % Change in Thyroglobulin (Suppressed) (Post-Selumetinib/pre-RAI vs post RAI) Thyroglobulin Changes % 80% 60% 40% 20% Mean TG Reduction: 91% 0% -20% -40% -60% -80% -100%

59 Preliminary Conclusions Selumetinib can induce/enhance iodine uptake in a subset of patients with RAI refractory thyroid cancer Selumetinib effects upon iodine uptake have been observed in both BRAF wild type and mutant tumors This protocol strategy can reduce tumor size(s) and decrease serum thyroglobulin Patients with RAI refractory tumors that are heterogeneous for iodine uptake and exhibit low FDG avidity may potentially be more susceptible to this strategy

60 Potential Future Directions Possible follow-up selumetinib (AZD6244) studies: Randomized study of RAI +/- selumetinib in metastatic/recurrent, RAI refractory thyroid cancer Randomized study of RAI +/- slumetinib in the adjuvant setting following resection of high risk thyroid cancer Testing alternate inhibitors of the MAPK pathway (BRAF, MEK inhibitors)

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